Abstract Herpesviruses are ubiquitous in humans and they have been implicated in diverse malignancies. Human Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus are associated with tumors of lymphoid, epithelial, and endothelial origin in immuno-compromised patients. The ability of these human pathogens to induce tumor formation is largely attributable to oncogene(s) that the viral genome contains. When expressed in cells, oncogenic viral polypeptides trigger cellular signaling cascades that culminate in promoting cell proliferation and survival. One of such viral signaling molecules is the KSHV G protein-coupled receptor (kGPCR). kGPCR is a seven-transmembrane protein that transmits signal across the plasma membrane. Despite being a functional homolog of the human IL-8 receptor, kGPCR is constitutively active independent of ligand binding. One key signaling pathway downstream kGPCR is the activation of nuclear factor of activated T cells (NFAT). However, how kGPCR regulates NFAT activation and the roles of NFAT in kGPCR tumorigenesis remain not well understood. In particular, the kGPCR-NFAT-chemokine circuitry fuels a feed-forward outcome, implying the existence of negative regulatory mechanisms. In this study, we propose to delineate the mechanism by which kGPCR explores a kinase and a metabolic enzyme to negatively regulate and tune NFAT activation, thereby promoting tumorigenesis. We will employ pharmacological agents to hyper-activate NFAT and thwart kGPCR tumor formation. Overall, our work will decipher the signaling labyrinth and develop a new antiviral and antitumor strategy targeting oncogenic GPCRs, instructing us on new means to treat KSHV-associated malignancies and other diseases related to NFAT activation.